We are interested in elucidating the mechanisms underlying olfactory sensory discrimination in mammals using the mouse as an experimental system. The remarkable discriminatory ability of the mouse olfactory system depends on a large family of 1,000 odorant receptor (OR) genes. We are studying how individual neurons specifically choose to express only one allele of the thousand distinct OR genes. This OR gene choice mechanism is of central importance to olfactory discrimination. In the previous funding period, we have advanced our knowledge of OR gene regulation and have discovered an unanticipated and exciting new mechanism of gene regulation. We have shown that in addition to OR genes, gene families essential to the immune system are asynchronously replicating. Our most striking data indicate that there is coordination along long distances of various chromosomes of this replication asynchrony of OR genes and other autosomal genes. Following on our previous observations, the specific aims of this grant are to: 1. Analyze allele-specific epigenetic changes at the P2OR gene cluster on mouse chromosome 7. These studies will include biochemical and molecular approaches to studying chromatin structure of OR genes and will take advantage of existing transgenic mice. 2. Study parallels to X-inactivation by studying the effects of aneuploidy of autosomes on OR gene regulation. 3. Determine whether the precursor cells that will ultimately give rise to mature olfactory neurons have already chosen the OR gene they will express. Understanding these mechanisms will be of value in understanding how olfactory discrimination occurs and in understanding how the regulation of gene expression allows for the remarkable diversity of olfactory neurons and perhaps other neurons.